Certain medications, especially those intended for the treatment of acute and chronic respiratory disorders, are most effective when inhaled directly into the lungs. Numerous pharmaceutical products are available for use as aerosols administered from metered dose inhalers. For example, bronchodilators are used in the treatment of bronchospasm and mucosal edema. Antibiotic aerosols are used to treat bronchial infections, anti-inflammatory steroids are used in the treatment of asthma, antifoaming agents are used in the treatment of fulminant pulmonary edema, and cromolyn sodium is used to control allergic asthma.
There is extensive literature indicating the successes of aerosol therapies, as well as the difficulties of using the aerosols properly. See, for example, Respiratory Infection: Diagnosis and Management, J. E. Pennington ed. Raven Press, N.Y.; Chest 1981, 80:911-915; Arch. Int. Med. 1973, 131:88-91.
Notwithstanding the very considerable development of aerosols and methods of using the same, there is still room for improvement in the administration of pharmaceutical aerosols. This is true not only in the case of drugs which are conventionally used in aerosol form but also to permit treatments which currently have to be conducted in some other less desirable fashion. Thus, improved and specific delivery of drugs in aerosol form to the lungs offers the possibility of therapies which are now considered impractical with other devices currently available. Polypeptides are made up of amino acid sequences, and include large molecules like insulin, and all of the products of recombinant DNA (rDNA) techniques. They are broken down in the digestive tract, and therefore the intact polypeptide molecule is not absorbed into the bloodstream. As a consequence, the only practical way to administer drugs of this type is by injection although nasal routes of administration have been suggested. It would be advantageous to provide an effective way of administering such a drug by way of the lungs.
Tissue plasminogen activator (t-PA) appears to be successful in halting damage done to cardiac muscle during myocardial infarction. There could be an advantage to be being able to carry this drug as an inhalant, and administering it without the need to wait for a physician or paramedic.
Delivery of therapy in pneumonia directly to the lung also has merit. Ordinarily, the concentration of antibiotic in the sputum is only two to three percent of the concentration in blood. In pneumonia or in cystic fibrosis, antibiotic concentration in the sputum is believed to be the determining factor for efficacy of the therapy.
A major problem of aerosol therapy is to deposit the aerosol on the walls of small bronchi and bronchioles, where the action of the medication is most often required. Less then ten percent of the medication delivered by standard metered dose inhalers reaches the typical patient's lungs. Most of the ninety percent of the medication which does not penetrate the target area is deposited in the mouth, throat, and trachea, and is eventually ingested. A small fraction of the aerosol is exhaled. The medication which deposits in the mouth and throat may lead to dysphonia and/or oral and laryngeal candidasis while the medication which is ingested serves no medical purpose to the patient, and is responsible only for undesirable side effects.
There are several problems to consider in the proper delivery of inhaled drugs to the lungs:
(1) The aerosol should consist of small particles, less than 5 microns, since larger particles cannot negotiate the sharp turns to the lung and are deposited in the oropharynx due to inertial effects. In order to minimize mouth deposition further it has been shown that the volumetric flow rate of the inhaled aerosol should be below 30 liters per minute.
(2) Metered dose inhalers deliver aerosol at a very high velocity directly into the patient's mouth where most of the medication impacts and is deposited in the mouth. This high initial velocity of the aerosol is a major factor in the ineffectiveness of many inhaler systems.
(3) Particles that persist in the airstream beyond the oropharynx may deposit on the larynx and on the walls of the trachea and of the large bronchi due to turbulence if the patient inhales at a volumetric flow rate above 30 liters per minute.
(4) In pulmonary physiology, the term "vital capacity" is the volume of air a patient can voluntarily exhale after having inhaled to total lung capacity. The vital capacity can vary from 2 to 5 liters depending on fitness, disease, gender, and age. It has been shown that in order to obtain maximum benefit from inhaled aerosols, the medication should be inspired after the patient has inhaled to at least 20 percent of his vital capacity. There is lack of agreement on the precise optimum, with the extremes being from 20 percent to 80 percent of vital capacity. In any case, after the medication has been inhaled, it is best to continue inhaling to total lung capacity, followed by holding of the breath for four to ten seconds, if possible.
(5) The device should limit the volumetric flow rate of the medication and aerosol as they enter the mouth, and should also allow the medication to be inhaled at a predetermined point in the respiratory cycle. Additionally the device should make it possible to inhale to total lung capacity. Furthermore, the size of the device should allow the user to carry the device around without too much inconvenience, and the cost to the patient should also obviously be low.
The medication delivery system of the present invention meets all of the above criteria. It is based on work done to image the deposition of aerosol medications in the human lung. This work utilized aerosol medications tagged with radioactive emitters, and used some of the currently available inhalation aids which are described hereinafter.